TARCEVA® (erlotinib HCI) is a tyrosine kinase inhibitor (TKI). As referenced in the FDA-approved label, TARCEVA® is indicated in the United States for first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test; maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum based first-line chemotherapy; treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen; and first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine.
TARCEVA® (erlotinib), a tyrosine kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA® contains erlotinib as the hydrochloride salt that has the following structural formula:
Reference is made to U.S. RE 41,065, herein incorporated by reference with regard to the description and synthesis of the compound.
Erlotinib hydrochloride has the molecular formula C22H23N3O4.HCl and a molecular weight of 429.90. The molecule has a pKa of 5.42 at 25° C. Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate, and hexane. Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2.
Epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells. In some tumor cells signaling through this receptor plays a role in tumor cell survival and proliferation irrespective of EGFR mutation status. Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thereby inhibiting further downstream signaling. Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 (L858R) mutations is higher than its affinity for the wild type receptor. Erlotinib inhibition of other tyrosine kinase receptors has not been fully characterized.
As with other ATP competitive small molecule tyrosine kinase inhibitors, patients may develop resistance. Over 50% of resistance is caused by a mutation in the ATP binding pocket of the EGFR kinase domain involving substitution of a small polar threonine residue with a large nonpolar methionine residue, T790M. See, Balak et al., Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors, Clin. Cancer Res 12 (1): 6494-501, (2006). While proponents of the ‘gatekeeper’ mutation hypothesis suggest this mutation prevents the binding of erlotinib through steric hindrance, research suggests that T790M confers an increase in ATP binding affinity, thereby reducing the inhibitory efficacy of erlotinib. See, Yun et al., The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, PNAS 105 (6): 2070-5, (2008).
EGFR-mutant lung cancers are highly responsive to EGFR tyrosine kinase inhibitors (TKIs) with superior progression free survival when compared to cytotoxic chemotherapy. See, for example, Lee et al., Impact of Specific Epidermal Growth Factor Receptor (EGFR)Mutations and Clinical Characteristics on Outcomes after Treatment with EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis, Journal of clinical oncology. 2015; 33(17):1958-65; Mok et al., Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, The New England Journal of Medicine, 2009; 361(10):947-57; Rosell et al., Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3trial, The Lancet Oncology, 2012; 13(3):239-46; and Sequist et al., Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations, Journal of Clinical Oncology, 2013; 31(27):3327-34. The majority of patients will respond to erlotinib, gefitinib, and afatinib, but in less than a year develop resistance to further therapy with these agents. See, Sequist et al., Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations, Journal of Clinical Oncology. 2013; 31(27):3327-34; Maemondo et al., Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, The New England Journal of Medicine, 2010; 362(25):2380-8; Mok et al., Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N. Engl. J. Med., 2009; 361(10):947-57; and Janne et al., Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406Trial, Journal of Clinical Oncology, 2012; 39(17): 2063-9. As noted hereinabove, the most common mechanism of resistance is acquisition of an EGFR T790M mutation, identified in 60% of patients with acquired resistance to EGFR TKIs. See also, Kobayashi et al., EGFR mutation and resistance of non-small-cell lung cancer to gefitinib, The New England Journal of Medicine. 2005; 352(8):786-92, and Yu et al., Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers, Clinical Cancer Research, 2013, 19(8):2240-7. Acquired resistance occurs, however, with the central nervous system as a frequent site of relapse. A parallel strategy to improve outcomes in patients with EGFR-mutant lung cancers is to adjust initial treatment to delay or prevent acquired resistance. While some have investigated EGFR TKIs in combination with other agents, modulating EGFR TKI dosing to prevent resistance in patients with EGFR-mutant lung cancers has not been assessed. See, Johnson et al., Phase I/II Study of HSP90Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to 18 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, Journal of Clinical Oncology, 2015, 33(15):1666-73, Riely et al., Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus, Clinical Cancer Research, 2007, 13(17):5150-5, Reguart et al., Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression, Lung Cancer, 2014, 84(2):161-7, Johnson et al., Phase II trial of dasatinib for patients with acquired resistance to treatment with the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib or gefitinib, Journal of Thoracic Oncology. 2011, 6(6):1128-31, and Goldberg et al., A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer, Journal of Thoracic Oncology, 2012, 7(10):1602-8. Third generation EGFR TKIs, such as osimertinib, which inhibit EGFR T790M may be effective at the time of progression on erlotinib, afatinib, or gefitinib.
Erlotinib was initially developed to inhibit wild-type EGFR. The 150 mg daily dose was the maximum tolerated dose established via a phase I study (Hildalgo et al.), which predated knowledge of EGFR mutation. The choice of a 150 mg daily dose, therefore, did not take into consideration the development of drug resistance in patients whose tumors harbor EGFR mutations. Hidalgo et al., Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced solid malignancies, Journal of Clinical Oncology, 2001, 19(13):3267-79. Mathematical modeling can predict the evolutionary dynamics that result in proliferation of resistant clones, and suggest potential alternative dosing schedules to delay resistance. See, Chmielecki et al., Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling, Science Translational Medicine, 2011, 3(90):90ra59, and Foo et al., Evolution of resistance to targeted anti-cancer therapies during continuous and pulsed administration strategies, PLoS Computational Biology, 2009, 5(11):e1000557. Yu et al., used these methods to evaluate different dosing schedules of erlotinib and selected twice weekly high dose of erlotinib plus daily low dose erlotinib as better able to delay progression in the setting of pre-existing resistant, EGFR T790M positive cells. The mathematical prediction and hypotheses were confirmed in pre-clinical studies using 20 μM erlotinib/1 μM erlotinib and 100 nM afatinib/1 μM erlotinib doses. See, Chmielecki et al., Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling, Science Translational Medicine, 2011, 3(90):90ra59.
Milton et al., conducted a study of weekly high dose erlotinib in unselected patients with advanced lung cancers. See, Milton et al., Weekly high-dose erlotinib in patients with non-small cell lung cancer (NSCLC): a phase I/II study, Cancer, 2006; 107(5):1034-41. The maximum tolerated dose (MTD) was not reached at erlotinib 2000 mg once weekly. A separate Phase 1 study of twice-weekly pulse dose erlotinib identified the MTD to be erlotinib 1000 mg twice-weekly, with a DLT of rash seen at higher dose levels. See, Chia et al., A Phase 1 dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twice weekly erltoinib in advanced stage malignancies, Journal of Clinical Oncology, 2007:25, Suppl; Abstract 3594.
Due to a wide inter-subject variability in bioavailability, lower daily doses of erlotinib may be effective with significantly less toxicity, although not proven in a randomized trial setting. Yamada et al., A prospective, multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911, Eur J Cancer, 2015 September; 51(14): 1904-10; Erlotinib ata dose of 25mg daily for non-small cell lung cancers with EGFR mutations, Journal of Thoracic Oncology, 2010; 5(7):1048-53; and Satoh et al., Low-dose gefitinib treatment for patients with advanced non-small cell lung cancer harboring sensitive epidermal growth factor receptor mutations. Journal of Thoracic Oncology, 2011; 6(8):1413-7.
The available data suggest that EGFR TKI high pulse dosing is tolerable and low daily dosing is effective but these have not previously been administered together in patients.
Central nervous system (CNS) involvement is a major issue for patients with EGFR-mutant lung cancers, with up to sixty percent of these patients developing brain or leptomeningeal metastases during their disease course. See, Heon et al., The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations, Clinical Cancer Research, 2012; 18(16):4406-14; and Omuro et al., High incidence of disease recurrence in the brain and leptomeninges in patients with non-small cell lung carcinoma after response to gefitinib, Cancer, 2005, 103(11):2344-8. Although benefit is commonly seen with EGFR TKIs when CNS disease is already present, these medications inconsistently lead to durable CNS control and do not prevent the emergence of CNS metastases. Up to 33% of patients with EGFR-mutant lung cancers have CNS progression during initial EGFR TKI therapy and in a significant subset of patients, the CNS progression occurs in the setting of continued systemic control. See, Heon et al., The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations, Clinical Cancer Research, 2012, 18(16):4406-14; Omuro et al., High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib Cancer, 2005; 103(11):2344-8; and Lee et al., Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer, Cancer, 2010, 116(5):1336-43. Central nervous system-only progression may be a result of inadequate brain penetration, with cerebrospinal fluid (CSF) concentrations of erlotinib only 3-5% of those in plasma. See, Togashi et al., Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer, Journal of Thoracic Oncology, 2010, 5(7):950-5.